Local C1q/TNF-related protein 1 attenuates kidney inflammation and fibrosis by regulating macrophage activation.

Abstract

Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related protein 1 (CTRP1) plays a potential role in fibrosis and inflammation in other tissues, we investigated the role of CTRP1 in patients and mice with CKD. Here CTRP1 expression was increased in plasma and decreased in the kidneys of patients with CKD. Upregulation of renal CTRP1 with adeno-associated-CTRP1 was associated with decreased renal fibrosis, inflammation, macrophage accumulation, and activation in mice models. Mechanistically, CTRP1 abolished the expression of transforming growth factor beta 1 (TGFβ1)-induced macrophage M2-associated genes and the transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). In addition, upregulation of CTRP1 could partly downregulate lipopolysaccharide (LPS)-stimulated expression of proinflammatory genes in vitro. Conditioned media from TGFβ1-CTRP1-pretreated macrophages could less efficiently stimulate fibroblast activation compared with those from TGFβ1-pretreated macrophages. Thus, our study reveals local CTRP1 as a potential regulator of chronic inflammation and kidney fibrosis through regulating macrophage activation. Taken together, these findings support renal CTRP1 as a novel therapeutic target for CKD.NEW & NOTEWORTHY Augmenting renal CTRP1 expression mitigates chronic inflammation and fibrosis by inhibiting pathological macrophage activation. These findings offer a novel mechanism of kidney inflammation and fibrosis. CTRP1 can be considered as a predictive marker and/or therapeutic target for patients with CKD.